With the on-going advance in mean age of the population and changing dietary habit, the number of patients with arteriosclerosis and associated coronary or cerebral arterial disease is on the steady increase. While a number of etiologic factors has been suggested in the oneset of arteriosclerosis, elevation of blood cholesterol is regarded as one of chief causative factors and it is being made increasingly clear that for the prevention and treatment of arteriosclerosis, a drug capable of lowering blood cholesterol is effective.
For the pharmacotherapy of hyperlipidemia, available in the main are blood cholesterol-lowering compositions comprising, as active ingredients, fibrates such as clofibrate, simfibrate, clinofibrate, bezafibrate, etc.; nicotinic acid and its derivatives such as nicomol, niceritol, etc.; dextran sulfate; cholestyramine; probucol; 3-hydroxymethylglutaryl(HMG)CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, etc. [Mizushima, Y. & Miyamoto, A: "Konnichino-Chiryoyaku, Kaisetsu-to-Binran (Therapeutic Drugs Today, Comments and Guides) '97", pp. 419-426, Nankodo]. Among those blood cholesterol-lowering compositions, those comprising cholesterol biosynthesis inhibitors, namely HMG-CoA reductase inhibitors, are clinically highly valued because of their well-defined mechanisms of action and remarkable efficacy.
While those drugs are capable of lowering the blood concentration of cholesterol, they have risks for adverse reactions.
As side effects of fibrates, liver impairment, cholelithiasis, myositis, granuloblastosis, rhabdomyolysis, etc. have been reported.
As typical side effects of nocotinic acid derivatives, facial flush, rash, headache, and vomiting are known.
As side effects of HMG-CoA reductase inhibitors, liver impairment, rhabdomyolysis, elevation of creatine kinase (CPK), diarrhea, abdominal pain, etc. are known.
Even with cholestyramine and probucol, which are comparatively free from side effects, liver impairment and elevation of CPK are known to occur.
Hyperlipidemia in many cases is hyperlipidemia secondary to nephrotic syndrome, obstructive biliary tract disease, hypothrea, or diabetes and many of such patients have diseases other than hyperlipidemia as well. Thus, the recommended therapy for such patients begins with dietetic treatment and ergotherapy, followed by the above drug therapy depending on the time course of serum lipid. If any one drug fails to produce a sufficient response, a combined therapy using a plurality of drugs differing in the mechanism of action is carried out and favorable responses are then obtained in many cases. Thus, a plurality of drugs are used in patients with hyperlipidemia but the risk for drug interactions and potentiation of adverse reactions is increased. For example, the therapy using a fibrate and an HMG-CoA reductase inhibitor may induce rhabdomyolysis and associated acute renal failure.
Meanwhile, cholesterol biosynthesis starts with the synthesis of HMG-CoA from acetyl-CoA and acetoacetyl-CoA and reduction of the HMB-CoA by HMG-CoA reductase to mevalonic acid. Then, starting with mevalonic acid, synthesized are important physiological metabolites such as the cell membrane component sterol; heme A and coenzyme Q, which are involved in electron transport system; dolichol, which is necessary for glycoprotein synthesis; isopentyladenine for transfer RNA; various intracellular signal transporters; and steroid hormones. This process is known as the mevalonic acid pathway [J. L. Goldstein and M. S. Brown, Nature, 343, pp. 425-430, 1990].
Since HMG-CoA reductase mentioned above is a rate-determining enzyme involved in a comparatively early stage of cholesterol biosynthesis, any HMG-CoA reductase inhibitors can be utilized as a cholesterol-lowering agent. However, HMG-CoA reductase inhibitors represented by lovastatin inhibit synthesis of coenzyme Q at the same time [E. L. Appelkvist et al., Clinical Investigator, 71, pp. S97-S102, 1993] and the physiological coenzyme Q level is decreased as a consequence. As a possible cause, it is suspected that the mevalonic acid pathway is shared by coenzyme Q biosynthesis and cholesterol biosynthesis in common.
Japanese Kohai Publication Hei-2-233611 discloses a method comprising using coenzyme Q.sub.10 in combination with an HMG-CoA reductase inhibitor in order to make up for the decrease in coenzyme Q.sub.10 caused by an HMG-CoA reductase inhibitor.
A. M. Bargossi et al. report cases in which the combined use of an HMG-CoA reductase inhibitor and coenzyme Q.sub.10 precluded the decline in coenzyme Q.sub.10 [Molecular Aspects of Medicine, 15, pp. S187-S193, 1994]. Thus, while simvastatin monotherapy causes not only a fall in blood cholesterol but also a decrease in blood coenzyme Q.sub.10, the combined therapy with simvastatin and coenzyme Q.sub.10 may lead to a rise in blood coenzyme Q.sub.10 without sacrificing the blood cholesterol-lowering effect of simvastatin. However, the dosage of coenzyme Q.sub.10 in this combined therapy is the dosage required to make up for the decrease in coenzyme Q.sub.10 without affecting the cholesterol-lowering action of the cardinal drug and is irrelevant to the effective dosage of coenzyme Q.sub.10, i.e. use of coenzyme Q.sub.10 as an independent active ingredient.